Stability of irinotecan-loaded drug eluting beads (DC BeadTM) used for transarterial chemoembolization

Abstract

Purpose. The aim of this study was to determine the loading efficiency, physicochemical stability, and release of irinotecan-loaded DC Beads^TM (bead size 100—300 μm, 300—500 μm) before and after mixing with nonionic contrast medium (Accupaque^® 300, Imeron^® 300, Ultravist ^® 300) during a prolonged period of time (28 days) when stored at room temperature or refrigerated.

Methods. DC Beads ^TM were loaded with 50 mg irinotecan (Campto^®) per milliliter beads in a 2 h loading period. Drug loading efficiency and stability were determined by measuring the irinotecan concentration in the excess solution. A free-flowing in vitro elution method for a period of 2 h and phosphate buffered solution (PBS, pH 7.2) as elution medium were used to analyze the integrity of the irinotecan-loaded. Stability of irinotecan-loaded beads after mixing with an equal volume of three different nonionic contrast agents was determined by measuring irinotecan concentrations in the excess solutions. Vials with loaded beads were stored protected from light at room temperature. Mixtures with contrast media were stored protected from light under refrigeration (2—8°C). Samples were taken periodically over a 4 week period (day 0, 1, 3, 7 and 28). A reversed phase HPLC assay with ultraviolet detection was utilized to analyze the concentration and purity of irinotecan.

Results. The loading procedure of DC Beads^TM with irinotecan drug solution resulted in a loading percentage of 96% (bead size 100—300 μm) independent of the storage time. No differences in loading levels and no irinotecan degradation products were observed over the period of 28 days, while the test vials were stored light protected at room temperature. Integrity of loaded irinotecan was also given over that same period of time according to the purity and concentration of irinotecan measured after intentional elution with PBS. Mixing of irinotecan-loaded beads (bead size 100—300 μm, 300—500 μm) with nonionic contrast media decreased the irinotecan loading efficiency by ∼5—10% during a maximum period of 24 h. However, no further elution or degradation was observed during a 4-week period when stored protected from light under refrigeration.

Conclusions. Irinotecan-loaded DC Beads^TM are shown to have adequate physicochemical stability over a period of at least 28 days when stored light protected at room temperature. Due to concerns of microbiological overgrowth refrigeration should always be considered. The preparation of admixtures of irinotecan-loaded beads with contrast medium in centralized cytotoxic preparation units is not recommended, because of rapid elution of 5—10% of irinotecan from the loaded beads. Furthermore, physicians see no advantages of admixtures due to the wide variation of mixing ratios of drug-loaded beads with contrast medium. In addition varying volumes of 0.9% sodium chloride solution are to be admixed during the chemoembolization procedure